Hypotheses, Design, and Methods for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial

Hypotheses, Design, and Methods for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial Maria Mori Brooks, PhD,a,* Robert L. Frye, MD,b Saul Genuth, MD,c Katherine M. Detre, MD, DrPH,a,† Richard Nesto, MD,d Burton E. Sobel, MD,e Sheryl F. Kelsey, PhD,a Trevor J. Orchard, MBBCh, MMed Sci,f for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial Investigators‡ The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) is a National Institutes of Health (NIH)–sponsored randomized clinical trial that evaluates treatment efficacy for patients with type 2 diabetes mellitus and angiographically documented stable coronary artery disease. Using a 2ⴛ2 factorial design, BARI 2D compares revascularization combined with aggressive medical treatment versus aggressive medical treatment alone; simultaneously, BARI 2D compares 2 glycemic control strategies, insulin sensitization versus insulin provision. All patients have goals of glycosylated hemoglobin values <7.0% and uniform control of hypertension, dyslipidemia, and obesity following recommended medical guidelines. The primary end point of BARI 2D is all-cause 5-year mortality analyzed by intention to treat, and the principal secondary end point is the combination of death, myocardial infarction, and stroke. A total of 2,368 patients have been enrolled at 49 clinical centers throughout North America, South America, and Europe. The study enrollment period was January 2001 through March 2005, and the patient treatment and follow-up phase is expected to extend at least through May 2007. Participants are treated at the local BARI 2D clinical sites on a monthly basis for the first 6 months and then every 3 months until the end of the study. Within BARI 2D, central management centers oversee the control of glycemia, plasma lipid levels, hypertension, and obesity. The randomized clinical trial collects data on patient symptoms, clinical measurements, medications, and clinical events as well as data from centralized evaluations of angiograms, electrocardiograms, nuclear stress tests, blood and urine specimens, and relative economic costs. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;97[suppl]:9G–19G)

a Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; bMayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota, USA; cCase School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; dHarvard Medical School, Boston, Massachusetts, Lahey Clinic Medical Center, Burlington, Massachusetts, USA; e University of Vermont College of Medicine, University of Vermont, Burlington, Vermont, USA; fDepartment of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. Major funding for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial comes from a cooperative agreement with the National Heart, Lung, and Blood Institute (NHLBI). The core laboratories for electrocardiography (Dr. Bernard Chaitman, St. Louis University), economics (Dr. Mark A. Hlatky, Stanford University), and fibrinolysis (Dr. Burton E. Sobel, University of Vermont) were funded, respectively, by Grant Nos. U01 HL061746, U01 HL061748, and U01 HL063804 from the National Institutes of Health. The Nuclear Cardiology Core Laboratory (Dr. Ami E. Iskandrian, University of Alabama at Birmingham) received funding from Astellas Pharma US, Inc. *Address for reprints: Maria Mori Brooks, PhD, Assistant Professor, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 127 Parran Hall, 130 DeSoto Street, Pittsburgh, Pennsylvania 15261. E-mail address: [email protected]. † Deceased. ‡ A complete list of the BARI 2D Investigators is provided in the Appendix.

0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.02.023

The primary aim of the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial is to determine the optimal 5-year treatment for patients with type 2 diabetes mellitus and documented stable coronary artery disease (CAD) in the setting of uniform glycemic control and intensive management of other risk factors, including dyslipidemia, hypertension, tobacco smoking, and obesity. BARI 2D simultaneously tests the following 2 treatment efficacy hypotheses: 1. Coronary revascularization hypothesis: A strategy of initial elective revascularization of choice (surgical or catheter-based), combined with aggressive medical therapy, results in lower long-term mortality compared with a strategy of aggressive medical therapy alone. 2. Method of glycemic control hypothesis: With a target glycosylated hemoglobin (HbA1c) level of ⬍7.0%, a strategy of hyperglycemia management directed at insulin sensitization results in lower long-term mortality compared with a strategy of insulin provision. www.AJConline.org

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Figure 1. Organizational structure of the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D). NHLBI ⫽ National Heart, Lung, and Blood Institute; NIDDK ⫽ National Institute of Diabetes, Digestive, and Kidney Diseases.

Research Design and Methods Organizational structure: BARI 2D is a National Institutes of Health (NIH)–sponsored randomized clinical trial that includes 49 clinical sites throughout North America, South America, and Europe. The study is coordinated at the University of Pittsburgh (Pittsburgh, PA). Four management centers oversee risk-factor treatment of the BARI 2D patients, and 6 core laboratories collect and analyze supplementary data (Figure 1). Timeline: Recruitment began at 7 vanguard clinical sites on January 1, 2001. The remainder of the clinical sites began recruiting patients after April 1, 2001. The BARI 2D recruitment period extended until March 31, 2005, and patient follow-up and treatment is expected to continue through at least May 31, 2007. The study population for BARI 2D is 2,368 patients, and the projected mean follow-up per patient is ⱖ3.8 years. Patient eligibility criteria: The target study population for the BARI 2D trial is patients with a diagnosis of type 2 diabetes and angiographically documented CAD for which revascularization is not required for prompt control of severe or unstable angina. Determination of suitability for BARI 2D was made by a physician-investigator at each participating institution. The specific inclusion and exclusion criteria for BARI 2D participants are summarized in Table 1. Patients being treated with insulin or oral hypoglycemic drugs were eligible for BARI 2D, as well as patients treated with diet and exercise alone, provided that a diagnosis of diabetes can be confirmed by a review of medical records or can be made based on plasma glucose measurements. In BARI 2D, type 2 diabetes is defined by any one of the following: ●

Confirmed (ie, ⱖ2 readings) fasting plasma glucose ⬎125 mg/dL (⬎6.94 mmol/L)

● ● ●

●

Random plasma glucose ⱖ200 mg/dL (ⱖ11.1 mmol/L) Plasma glucose ⱖ200 mg/dL (ⱖ11.1 mmol/L) 2 hours following ingestion of 75 g of glucose Current treatment with diet or oral agents for the control of hyperglycemia, either alone or in combination with insulin Current treatment with insulin and no previous history of diabetic ketoacidosis.

Since patients with type 1 diabetes mellitus are excluded, the principal investigators were encouraged to obtain testing for C peptide, antibodies to glutamic acid decarboxylase, or proinsulin on a selected-case basis if there was clinical uncertainty. In BARI 2D, eligible patients must have been suitable for percutaneous coronary intervention (PCI) or for coronary artery bypass graft (CABG) surgery, but they need not have been suitable for both revascularization procedures. Significant CAD is defined as ⱖ1 stenosis of ⱖ50%. Angina and ischemia were assessed by use of patient self-report, physician examination, and appropriate diagnostic measures, including exercise myocardial perfusion imaging, exercise echocardiography, stress echocardiography, exercise electrocardiography (ECG), and intravenous dipyridamole or adenosine myocardial perfusion imaging, or invasively by Doppler guidewire. In borderline lesions, assessment of flow reserve by a Doppler guidewire in the coronary artery might be used to determine severity of ischemia and jeopardized myocardium. Objective documentation of myocardial ischemia included any of the following: 1. Findings induced by exercise or pharmacologic means a. ⱖ1 mm of horizontal or downsloping ST-segment depression or elevation for ⱖ60 – 80 msec after the end of the QRS complex b. Myocardial perfusion defect

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Table 1 Inclusion and exclusion criteria for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial Inclusion criteria ● Diagnosis of type 2 diabetes mellitus ● Coronary arteriogram showing ⱖ1 vessel amenable to revascularization (ⱖ50% stenosis) ● Objective documentation of ischemia or subjectively documented typical angina with ⱖ70% stenosis in ⱖ1 artery ● Suitability for coronary revascularization by ⱖ1 of the available methods (does not require the ability to achieve complete revascularization) ● Ability to perform all tasks related to glycemic control and risk-factor management ● Age ⱖ25 years ● Informed written consent Exclusion criteria ● Definite need for invasive intervention as determined by the attending cardiologist ● Prior bypass graft surgery or catheter-based intervention within the past 12 months ● Planned intervention for disease in bypass graft(s) if the patient is randomized to a strategy of initial revascularization ● New York Heart Association functional class III or IV congestive heart failure ● Plasma creatine ⬎2.0 mg/dL (⬎176.8 ␮mol/L) ● Glycosylated hemoglobin (HbA1c) ⬎13% ● Need for major vascular surgery concomitant with revascularization (eg, carotid endarterectomy) ● Left main coronary artery stenosis ⱖ50% ● Noncardiac illness expected to limit survival ● Hepatic disease (alanine aminotransferase ⬎2 times the upper limit of normal) ● Fasting plasma triglycerides ⬎1,000 mg/dL (⬎11.3 mmol/L) in the presence of moderate glycemic control (HbA1c ⬍9.0%) ● Current alcohol abuse ● Chronic steroid use judged to interfere with the control of diabetes (prednisone ⬎10 mg/day or the equivalent) ● Pregnancy, known, suspected, or planned in next 5 years ● Geographically inaccessible or unable to return for follow-up ● Enrolled in a competing randomized trial or clinical study ● Unable to understand or cooperate with protocol requirements

c. Myocardial wall motion abnormality d. Decline in left ventricular ejection fraction with stress 2. Stabilized, prior acute coronary syndrome with a. Elevation of creatine kinase (myocardial fraction) or troponin b. New, ⱖ0.5 mm ST-segment depression or elevation c. T-wave inversion of ⱖ3 mm in 2 contiguous ECG leads 3. Doppler guidewire showing coronary flow reserve ⬍2.0 or fractional flow reserve ⬍0.75. Among patients without documented ischemia, only patients with stenosis ⱖ70% presenting with classic anginal symptoms were eligible for randomization. If a patient had a history of CABG, the intended revascularization for BARI 2D must have involved only the native vessel(s); in particular, there should have been no plan for the intervention to involve the graft(s) during the initial revascularization. Patients with significant left main CAD were excluded from the trial, with 1 exception: patients with previous CABG who had a protected left main coronary artery (ie, graft[s] sufficient to protect the left coronary circulation) may have been eligible for the study.

Recruitment process: Due to differences among clinical sites regarding referral patterns and accessibility to information about potential patients, the screening process varied from site to site. In general, screening included identifying patients with diabetes who were having coronary angiography or testing for myocardial ischemia as part of standard clinical care. If patients were clinically eligible and their angiograms indicated that they were appropriate candidates for the study, then these patients may have been randomized. The screening process also focused on patients who were found to have an underlying diagnosis of diabetes while undergoing cardiac studies. Patient recruitment in BARI 2D generally began in the cardiac catheterization laboratory; the cardiac stress laboratory; or the cardiac, diabetes, or general medicine outpatient clinics. A patient may have been either referred by an outside physician who is familiar with the trial or self-referred after seeing recruitment materials or articles about the trial. The NIH made a strong commitment to enrolling minorities in clinical trials. Most NIH studies require that enrollment from minority populations be ⱖ20% of all participants. The BARI 2D trial aimed to recruit ⱖ30% of all trial participants from minority populations.

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Table 2 Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) randomization scheme: percentage of patients per treatment assignment Diabetes: Glycemic Control Strategy

Insulin providing Insulin sensitizing

Cardiology: Ischemic Control Strategy Revascularization*

Medical

25% 25%

25% 25%

* Coronary artery bypass graft surgery or percutaneous coronary intervention with medical therapy.

All patients must have signed an informed consent form before randomization; frequently patients signed the form during the screening process before undergoing angiography. The BARI 2D informed consent form included Health Insurance Portability and Accountability Act (HIPAA) authorization as well as separate consent for participation in the economics study and for participation in the BARI 2D genetics protocol. Randomization: The BARI 2D trial has a 2⫻2 factorial design, with patients assigned at random to initial elective revascularization with aggressive medical therapy versus initial aggressive medical therapy alone while simultaneously assigned at random to an insulin-providing versus an insulin-sensitizing strategy of glycemic control (with a target value for HbA1c of ⬍7.0% for all patients). Following confirmation of patient eligibility and provision of written consent, patients were randomized to 1 of the 4 treatment combinations shown in Table 2. Randomization was stratified by clinical site and by intended revascularization treatment (ie, PCI-intended or CABG-intended if randomized to revascularization). When performing the primary randomized treatment comparisons, the clinical site stratification was to be used to control for variation in treatment implementation and patient population between clinical sites. The stratification by intended revascularization treatment allowed for a valid randomized comparison of PCI versus medical therapy among patients appropriate for PCI and a valid randomized comparison of CABG versus medical therapy among patients appropriate for CABG. BARI 2D interventions: Aggressive medical therapy and modifiable risk-factor intervention are provided for all BARI 2D patients.1 Every patient is actively treated for dyslipidemia, hypertension, and angina using medical therapy guidelines given in the protocol. In addition, the BARI 2D protocol includes programs aimed at smoking cessation, weight control, and exercise. Randomized interventions: Beyond the aggressive medical therapy and modifiable risk-factor interventions that all patients receive, the strategy for treating angina and ischemia was randomly assigned in BARI 2D.2 Patients assigned to the initial revascularization group received a

revascularization procedure performed by a certified operator or surgeon within 4 weeks of randomization. The procedure was surgical (CABG) or catheter-based (PCI) and was selected by the BARI 2D investigator on the basis of the individual patient’s clinical and angiographic presentation. Patients assigned to the initial medical group received aggressive medical therapy without an early revascularization procedure. Under some circumstances, as outlined in the protocol (eg, if symptoms worsen significantly), medically assigned patients may receive a revascularization procedure during the follow-up period of the trial; these patients continue to be treated with aggressive medical therapy and to be actively followed under the BARI 2D protocol. The glycemic goal for all BARI 2D patients is a target HbA1c ⬍7.0%. In BARI 2D, the method of achieving this glycemic goal was randomly assigned.3 Patients assigned to an insulin-providing strategy of glycemic control may be treated with sulfonylurea drugs, repaglinide, nateglinide, or insulin itself. Patients assigned to an insulin-sensitizing strategy may be treated with thiazolidinediones (glitazones) or metformin. The ␣-glucosidase inhibitors are considered neutral drugs and can be used with either treatment group. Patients with a persistent level of HbA1c ⬎8.0% while taking the assigned treatment are mandated to receive glucose-lowering drugs from the opposite treatment arm to bring HbA1c within the range of 7.0% to 8.0%. For example, patients assigned to the insulin-sensitizing strategy may require insulin; in these instances, an insulin-sparing approach (ie, that minimizes the amount of insulin given) will be followed. Clinic visits and patient follow-up: The BARI 2D team is responsible for aggressively treating CAD and diabetes risk factors for the duration of the study according to the BARI 2D protocol. The patients’ primary care physicians continue to manage all other medical problems. Within 1 week of patient randomization, the clinic diabetology investigator and the study diabetes nurse specialist initiated the diabetes therapy regimen and provided comprehensive diabetes care education, and the clinic cardiology investigator initiated the CAD medical therapy regimen based on specified target risk factor goals. In addition, the diabetologist, with the help of a study dietitian, outlined a dietary and exercise program designed to achieve the patient’s nutritional needs and ideal body weight, thereby facilitating optimal glucose control. The schedule depicting 5-year follow-up is summarized in Table 3. There are monthly clinic visits for the first 6 months and then quarterly visits for the remainder of the study to (1) obtain a patient history of glycosuria, hyperglycemia symptoms, and episodes of hypoglycemia; measure body weight and blood pressure; collect a fasting blood sample for determination of lipids, glucose, and HbA1c as well as fibrinolytic and hemostatic factors; and assess liver and kidney function; (2) document medications being taken by the patient for diabetes, hypertension, and dyslipidemia;

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Table 3 Data collection by follow-up visit in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Visit

Clinic visits Monitor diabetes and cardiac medications, adverse events, complications and symptoms; HbA1c, lipids, blood pressure Assess quality of life, neuropathy, concomitant diseases Core laboratories fibrinolysis PAI-1, t-PA, insulin NMR lipids Biochemistry HbA1c Lipids Urine (albumin/creatinine) Electrocardiography Resting electrocardiogram Nuclear cardiology Pharmacologic nuclear stress study Angiography Angiogram Economics Medical care utilization, hospital costs, employment status

Years 2–6

Baseline*

1 mo

2 mo

3 mo

4 mo

5 mo

6 mo

9 mo

1 yr

Quarterly

X

X

X

X

X

X

X

X

X

X

X

Semiannual

X

X

X X

X

X

X

X X

X

X X X

X

X

X X

X X X

X

X

X

Annual

X X

X

X

X

Year 3

X X

X

X

X

X

HbA1c ⫽ glycosylated hemoglobin; PAI-1 ⫽ plasminogen activator inhibitor–1; t-PA ⫽ tissue plasminogen activator. * Baseline measurements made within 1 week of study entry.

and (3) collect information about adverse clinical events, complications, and angina status. In addition to the patient’s regular clinic visits with the BARI 2D diabetology team, the BARI 2D cardiologist is expected to see the patient at least twice per year to ascertain control of angina symptoms and to review stress tests, risk-factor management, and any other relevant data obtained as part of each patient’s continuing clinical care. Blood and urine laboratory studies: Blood was drawn at baseline and sent to the blood core labs to assay HbA1c, fibrinolytic factors, and insulin. These samples were to be drawn again at 1 month, 3 months, 6 months, 1 year, and then semi-annually until the end of follow-up. Blood was to be drawn for lipid assays at baseline, 6 months, 1 year, and then annually for the remainder of the follow-up period. In addition, for patients who gave informed consent, cells from the baseline HbA1c specimen were collected and appropriately frozen, with the future goal of identifying possible genetic risk factors related to treatment efficacy, atherogenesis, and the occurrence of macrovascular events. Urine specimens were collected at baseline and scheduled annually throughout follow-up. They are assayed at the biochemistry laboratory for albumin and creatinine, and an albumin/creatinine ratio is calculated. Finally, ECG tracings were obtained at baseline and at 3 months, 1 year, and then annually thereafter; pharmacologic nuclear stress tests are performed at 1 and 3 years after randomization.

Outcome evaluation: The primary end point of BARI 2D is all-cause mortality, and the principal secondary end point is the composite of death, myocardial infarction (MI), or stroke. Classification of MI is based on the BARI 2D core laboratory evaluation of enzymes, symptoms, and ECG results. Other secondary end points to be evaluated include cardiac mortality, MI, stroke, the composite end point of death or MI, left ventricular function, extent of ischemia, plasminogen activator inhibitor–1 (PAI-1) antigen and activity, tissue plasminogen activator antigen, lipids measured by nuclear magnetic resonance, angina, and subsequent revascularization procedures (CABG and PCI). The rates of diabetes-specific complications, including retinopathy, nephropathy, neuropathy, and peripheral vascular disease, will also be evaluated. In addition to clinical end points, cumulative medical costs, cost-effectiveness, employment, and quality of life will be analyzed. Finally, other critical outcomes, including HbA1c levels, hypoglycemic events, blood pressure, and lipids (measured chemically), as well as drugs used for management of hyperglycemia, hypertension, and dyslipidemia, are considered to be intermediate or process outcomes rather than true study end points and are actively monitored by the BARI 2D management committees during the trial. Patient subgroups: The primary treatment comparisons will also be tested in a limited number of predetermined subgroups. The BARI 2D a priori subgroups, defined by means of baseline factors, are intended method of revascu-

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larization, history of previous revascularization, receiving insulin at study entry, HbA1c level, left ventricular function, creatinine level, and race. Other prospectively identified baseline subgroup variables include sex, age, body mass index (BMI), number of diseased vessels, myocardial jeopardy, presence of diffuse disease, duration of diabetes, number of units of insulin received, presence of microalbuminuria, blood pressure, and low-density lipoprotein (LDL) level. Statistical analysis: All treatment comparisons will be made according to the intention-to-treat principle (ie, treatment assigned). Secondary analyses by treatment implemented may be appropriate in certain cases. The 2 primary randomized treatment comparisons from the 2⫻2 factorial design will be performed separately, each with a 2-sided ␣ ⫽ 0.05. The primary and principal secondary end points (survival and survival free of MI and stroke) will be evaluated with survival curves and stratified log rank statistics. The Data and Safety Monitoring Board (DSMB) meets every 6 months during the trial to review safety, efficacy, and adherence to protocol. Prespecified monitoring boundaries have been designated for the P values from the primary end-point treatment comparisons. Sequentially adjusted P values will be presented to the committee annually, and the DSMB may recommend terminating or modifying the trial on the basis of these analyses. For treatment comparisons within the a priori subgroups, a 2-sided ␣ ⫽ 0.01 will be used to correct for multiple testing; these comparisons will have less power than the full-scale comparison because of smaller sample sizes and stricter ␣ levels. Multivariable models that include “randomized treatment by subgroup” interactions will be used to test whether the treatments have different effects on outcome depending on the values of specified subgroup variables. In some models, the effects of time-dependent covariates may be assessed, including but not limited to insulin use and dosage; individual insulin-sensitizing drug use; HbA1c levels; LDL and other lipid levels; blood pressure; weight gain/BMI; use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins); and use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and ␤-adrenergic blockers. Original sample size and power estimates for BARI 2D were based on the assumptions that 2,800 patients would be recruited, an equal number of patients would be assigned to each treatment arm, there would be a 5-year average follow-up per patient, 5% of patients would eventually be lost to follow-up, and that ␣ ⫽ 0.05 for the primary treatment comparison. Given that 2,368 patients were recruited and that the current projected average follow-up is 3.8 years per patient, the revised estimated power is 73% to detect a 30% reduction in mortality, assuming a 14% mortality rate for the reference group (specifically, 14% vs 9.8% mortality rates), and 83% to detect a 25% reduction in “survival free of MI and stroke,” assuming a 24% event rate for the

reference group (specifically, 24% vs 18% combined event rates).

Data Management and Computing Data are collected and entered remotely at the clinical centers using MATRIX, software developed by the BARI 2D Coordinating Center (Pittsburgh, PA). Database management and data entry systems monitor data accuracy, quality, and completeness as well as timeliness of both data collection and data entry. Data records routinely pass a comprehensive set of entry point edit checks, extensive intraform and interform editing, and monitoring procedures. The core of the BARI 2D information management and communications system is the BARI 2D Web site (www.bari2d.org). This Web site is the central location for retrieving and disseminating all study information, including operation memos, news bulletins, the study directory, and data integrity and compliance reports. A help desk system is accessible and managed through the Web site along with a summary of frequently asked questions. The BARI 2D Web site is divided into a public domain and a private domain. Anyone can access the public domain and obtain information about the study. Only users with a Coordinating Center–assigned password can access the researchers’ private domain.

Organizational Units Administrative units: NIH PROGRAM OFFICE. BARI 2D is a cooperative agreement between the National Heart, Lung, and Blood Institute (NHLBI) and the University of Pittsburgh. As such, NHLBI members are closely involved with study operations. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) also provides financial support and scientific input for BARI 2D. OPERATIONS COMMITTEE. The Operations Committee is the study’s primary governing body. It is responsible for protocol design and operational concerns that require immediate action. The members of the Operations Committee come from the BARI 2D Steering Committee and include the NHLBI project officer, other representatives from the NHLBI, and the directors of the management centers. This group has weekly conference calls. Katherine M. Detre, MD, DrPH, was the principal investigator of the BARI 2D study and thus had the responsibility of overseeing all study activities. Sheryl F. Kelsey, PhD, assumed the role of principal study investigator upon Dr. Detre’s death. Robert L. Frye, MD, serves as the study chair and presides over the Steering Committee meetings and the weekly Operations Committee conference calls. Dr. Frye is responsible for reviewing all activities related to the design and implementation of BARI 2D. STEERING COMMITTEE. The Steering Committee consists of the principal investigators of each clinical site and of

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Table 4 Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) ancillary studies funded before January 2005 Ancillary Study Title Inflammation, Procoagulation, and Plaque Vulnerability Mechanisms of Pro-thrombosis in Diabetes Mellitus Platelet Function, GP IIIa Polymorphism, and PCl in BARI 2D Relation of Myocardial Insulin Resistance and Outcome in Type 2 Diabetes Mellitus with Coronary Artery Disease (PET Substudy) Impact of Health Literacy on Baseline Health Status, Protocol Compliance and Retention of Patients Enrolled in the BARI 2D Clinical Trial—A Single City Experience

Principal Investigator

Funding Institution

Burton E. Sobel, MD University of Vermont David J. Schneider, MD University of Vermont David J. Schneider, MD University of Vermont Panithaya Chareonthaitawee, MD Mayo Clinic–Rochester

National Heart, Lung, and Blood Institute

Tarek Helmy, MD Emory University

National Heart, Lung, and Blood Institute Centocor, Inc. American Heart Association

Emory University

GP IIIa ⫽ glycoprotein IIIa; PCl ⫽ percutaneous coronary intervention; PET ⫽ positron emission tomography.

each core lab; the principal investigator and co-investigators of the Coordinating Center; the directors of the diabetes, lipid, hypertension, and lifestyle intervention management centers; and the NIH representatives. This group, which meets twice per year, outlines broad study goals, determines study policies, reviews protocol implementation, and makes decisions about major issues that affect the BARI 2D trial. Operational units: COORDINATING CENTER, UNIVERSITY Dr. Detre, the BARI 2D principal investigator, directed all study related activities. She and the Coordinating Center investigators maintained professional relationships with the NHLBI, NIDDK, and the clinical investigators. They participate in decisions related to study design and data analysis for the trial, and they present data to the Steering Committee and DSMB. The Coordinating Center prepares all data reports for the study and works closely with investigators in manuscript preparation. CLINICAL CENTERS. In BARI 2D, there are 49 clinical sites in the United States, Canada, Mexico, Brazil, the Czech Republic, and Austria. Under the joint direction of a cardiologist and a diabetologist, each clinical center is responsible for the screening and recruitment of eligible patients, management of assigned glycemic treatment, performance of revascularization for those patients so assigned, and concomitant medical care for both ischemic symptoms and CAD risk-factor intervention as well as the collection and submission of all clinical and laboratory data required by protocol. OF PITTSBURGH.

Independent committees: DATA AND SAFETY MONITORNHLBI has appointed a DSMB to monitor and ensure the scientific integrity of the trial and to protect the safety of the patient participants. The DSMB approved the protocol and approves all protocol changes. The board reviews study recruitment, compliance, and all interim trial results; advises the NHLBI on important BARI 2D policy matters; and recommends continuation, modification, or termination of the trial at each DSMB meeting. ING BOARD (DSMB).

MORBIDITY AND MORTALITY CLASSIFICATION COMMITTEE. This committee reviews the primary end point data for

deaths and strokes. The members classify the cause of all

deaths, and they verify and categorize all strokes. They are blinded to treatment assignments. Management centers: DIABETES MANAGEMENT CENTER, CASE WESTERN RESERVE UNIVERSITY. The success of BARI 2D depends on the continuous reinforcement of medical guidelines prescribed for each patient from study entry to study end. To ensure this degree of medical involvement at the individual patient level, the Diabetes Management Center (Saul Genuth, MD, director) is responsible for overseeing protocol compliance by monitoring and insuring adherence to the glycemic control targets and medical treatment strategies. This center is assisted by a glycemic management committee of BARI 2D diabetology investigators. LIPID MANAGEMENT CENTER, UNIVERSITY OF PITTSBURGH. The Lipid Management Center (Trevor Orchard,

MBBCh, MMed Sci, director), regularly reviews lipid values and provides consultation to clinical sites regarding the management of individual patients and the overall clinical site lipid targets. HYPERTENSION MANAGEMENT CENTER, LAHEY CLINIC MEDICAL CENTER AND CORNELL MEDICAL CENTER. At the

Hypertension Management Center (Richard W. Nesto, MD, and Phyllis August, MD, co-directors), patient blood pressures and hypertension medications are reviewed regularly, and consultation is provided to sites that have not met individual patient or overall site blood pressure goals. LIFESTYLE INTERVENTION MANAGEMENT CENTER, ST. LUKE’S–ROOSEVELT HOSPITAL CENTER AND JOHNS HOPKINS BAYVIEW MEDICAL CENTER. The Lifestyle Intervention Man-

agement Center (Jeanine Albu, MD, and Sheldon H. Gottlieb, MD, co-directors), examines data regarding obesity, exercise level, and smoking status for clinical sites and individual patients. They work directly with the clinical sites to facilitate intensive and uniform lifestyle intervention. Core laboratories: CORE ECG LABORATORY, ST. LOUIS The Core ECG Laboratory (Bernard Chaitman, MD, principal investigator), interprets resting ECGs using uniform validated Novacode criteria, blinded to patient intervention. The laboratory analyzes baseline, UNIVERSITY.

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annual, postprocedure, and any other clinically indicated ECGs. In addition to the ECG data, the laboratory also collects information about enzymes and symptoms associated with suspected MIs and then classifies all suspected MI events. ECONOMICS CORE LABORATORY, STANFORD UNIVERSITY.

The Economics Core Laboratory (Mark A. Hlatky, MD, principal investigator), collects and analyzes data on medical care utilization and costs as well as patient employment status. To ascertain economic data, patients are contacted every 3 months by an interviewer at Stanford University and hospital bills are obtained.4 FIBRINOLYSIS AND COAGULATION CORE LABORATORY, UNIVERSITY OF VERMONT. The Fibrinolysis and Coagula-

tion Core Laboratory (Burton E. Sobel, MD, principal investigator), assesses tissue plasminogen activator and PAI-1 antigens and activity as well as insulin at baseline and throughout follow-up. Plasma is stored for future research requiring assessments of analytes that may be of interest but have not yet been delineated. BIOCHEMISTRY CENTRAL LABORATORY, UNIVERSITY OF MINNESOTA. The Biochemistry Central Laboratory (Mi-

chael W. Steffes, MD, PhD, principal investigator), analyzes HbA1c levels from blood samples. The laboratory also analyzes frozen blood and urine to obtain standardized lipid values and albumin/creatinine ratios. Cells from baseline HbA1c are stored for future genetics research. ANGIOGRAPHIC CORE LABORATORY, STANFORD UNIVERSITY. Baseline angiograms for all randomized patients

are interpreted by the Angiographic Core Laboratory (Edwin L. Alderman, MD, principal investigator), for lesion and procedure information. The laboratory also analyzes index PCI procedure angiograms for patients randomized to immediate revascularization. NUCLEAR CARDIOLOGY CORE LABORATORY, UNIVERSITY OF ALABAMA. The Nuclear Cardiology Care Laboratory

(Ami E. Iskandrian, MD, principal investigator), interprets the nuclear studies scheduled at 1 and 3 years as well as the clinically indicated unscheduled nuclear studies submitted by the clinical sites.

Ancillary Studies Currently, there are 5 active ancillary studies in BARI 2D (Table 4), and there may be several others before the end of the BARI 2D trial. These ancillary studies have been funded separately to collect additional data on some or all BARI 2D patients. These data will be analyzed along with baseline and follow-up data obtained from the full BARI 2D trial.5

Acknowledgments The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) study receives significant supplemen-

tal funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); GlaxoSmithKline (financial support, rosiglitazone, Coreg [carvedilol], and Avandamet [rosiglitazone and metformin]); BristolMyers Squibb Medical Imaging, North Billerica, Massachusetts (financial support and Cardiolite [sestamibi]); Fujisawa Healthcare, Inc.; and Pfizer, Inc. In addition, a number of pharmaceutical companies have donated drugs and/or supplies to BARI 2D, and these companies are: Abbott Laboratories, Inc.; Abbott Laboratories Ltd., MediSense Products; Bayer Diagnostics; Becton, Dickinson and Company; J. R. Carlson Labs; Centocor, Inc.; Eli Lilly and Company; Fujisawa Healthcare, Inc.; LipoScience, Inc.; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; and Pfizer, Inc. 1. Albu J, Gottlieb SH, August P, Nesto RW, Orchard TJ, for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial Investigators. Modifications of coronary risk factors. Am J Cardiol 2006;97(suppl 12A):40G–51G. 2. Barsness GW, Gersh BJ, Brooks MM, Frye RL, for the BARI 2D Trial Investigators. Rationale for the revascularization arm of the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D). Am J Cardiol 2006;97(suppl 12A):30G–39G. 3. Magee MF, Isley WL, for the BARI 2D Trial Investigators. Rationale, design, and methods for glycemic control in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. Am J Cardiol 2006;97(suppl 12A):19G–29G. 4. Hlatky MA, Melsop KA, Boothroyd DB, for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial Investigators. Economic evaluation of alternative strategies to treat patients with diabetes mellitus and coronary artery disease. Am J Cardiol 2006; 97(suppl 12A):59G– 65G. 5. Sobel BE, for the BARI 2D Trial Investigators. Ancillary studies in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial: synergies and opportunities. Am J Cardiol 2006;97(suppl 12A):52G–58G.

Appendix The BARI 2D Investigators: University of Pittsburgh, Pittsburgh, PA (Coordinating Center): (Principal Investigator) Katherine M. Detre, MD, DrPH,† (Co-Principal Investigator) Maria Mori Brooks, PhD, (Co-Investigators) David Kelley, MD, Sheryl F. Kelsey, PhD, Trevor J. Orchard, MBBCh, MMedSci, Stephen B. Thomas, PhD, Kim Sutton Tyrrell, RN, DrPH, Joseph Zmuda, PhD, Richard Holubkov, PhD, (Coordinator) Sharon Weber Crow, BS, (Administrative Coordinators) Michele Carion, Sharon Happe, Joy Herrington, MEd, Joan M. MacGregor, MS, Scott M. O’Neal, MA, Veronica Sansing, BA, Mary Tranchine, BS, (Statisticians) Regina Hardison, MS, Kevin Kip, PhD, Jiang Lu, MS, Manuel Lombardero, MS, (Data Managers) Sue Janiszewski, MSIS, Heather Luiso, BS, Sarah Reiser, BS, David Salopek, BS, (System Programmers) Stephen Barton, ASB, Yulia Kushner, BS, BA, Owen Michael, ASB, Juinn-Woei Pan, MSIS, Nicole Bartolowits, BS, (System Support) Jeffrey P. Martin, MBA, Christopher Kania, BS, Michael Kania, BS, Jeffrey O’Donnell, BS, (Consultant) Rae Ann Maxwell, RPh, PhD. Mayo Clinic Foundation, Rochester, MN: (Study Chair) Robert L. Frye, MD. Na†

Deceased.

Brooks et al/Hypotheses, Design, and Methods for the BARI 2D Trial

tional Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD (Program Office): (Project Officer) Suzanne Goldberg, RN, MSN, (Deputy Project Officer) Tracey Hoke, MD, ScM, (NHLBI Officers) Patrice Desvigne-Nickens, MD, Abby Ershow, ScD, David Gordon, MD, PhD, Dina Paltoo, PhD, MPH. National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD (Co-Funding): (Program Director for Diabetes Complications) Teresa L. Z. Jones, MD, Judith Fradkin, MD. University of Alabama at Birmingham, Birmingham, AL (Clinical Center, Vanguard Site): (Principal Investigators) Cardiology: William Rogers, MD; Diabetology: Fernando Ovalle, MD, David Bell, MBBCh, (Coordinators) Melanie Smith, RN, BSN, Ashley Vaughan, RN, BSN, Beth Barret, RN, Susan Rolli, RN. Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY (Clinical Center): (Principal Investigators) Cardiology: Scott Monrad, MD, Vankeepuram Srinivas, MD; Diabetology: Jill Crandall, MD, Joel Zonszein, MD, (Coordinators) Helena Duffy, ANP, CDE, Eugen Vartolomei, MD. Baylor College of Medicine, Houston, TX (Clinical Center): (Principal Investigators) Cardiology: Neal Kleiman, MD; Diabetology: Alan Garber, MD, (Coordinators) Maribel Henry, RN, BSN, Lynn Sue Felker, RN, Bella BellezaBascon, RN. Boston Medical Center, Boston, MA (Clinical Center): (Principal Investigators) Cardiology: Alice Jacobs, MD; Diabetology: Elliott Sternthal, MD, Susana Ebner, MD, (Coordinators) Monica Voudris, BS, Deborah Gannon, MS, Jamie Hutchinson, BS. University of British Columbia/Vancouver Hospital, Vancouver, British Columbia, Canada (Clinical Center): (Principal Investigators) Cardiology: Christopher Buller, MD; Diabetology: Tom Elliott, MBBS, (Coordinators) Rebecca Fox, PA, MSc, Rossali Pilapil-lee, MD. Brown University/Rhode Island Hospital, Providence, RI (Clinical Center): (Principal Investigators) Cardiology: David Williams, MD; Diabetology: Robert Smith, MD, Marc Laufgraben, MD, (Coordinators) Mary Grogan, RN, Janice Muratori, RNP. University of Chicago Medical Center, Chicago, IL (Clinical Center): (Principal Investigators) Cardiology: David Faxon, MD; Diabetology: Andrew Davis, MD, Sirimon Reutrakul, MD, (Coordinators) Peggy Bennett, RN, BSN, Melissa Hill, MS. University Hospitals of Cleveland/Case School of Medicine, Cleveland, OH (Clinical Center, Vanguard Site): (Principal Investigators) Cardiology: Dale Adler, MD; Diabetology: Faramarz Ismail-Beigi, MD, PhD, Suvinay Paranjape, MD, (Coordinators) Stacey Mazzurco, RN, Michael Borsich, RN, Karen Ridley, RN, BSN. Duke University, Durham, NC (Clinical Center): (Principal Investigators) Cardiology: Christopher Granger, MD; Diabetology: Mark Feinglos, MD, Jennifer Green, MD, (Coordinators) Ronna Bakst, MS, RD, LDN, CDE, Dani Underwood, MSN, ANP. Emory University, Atlanta, GA (Clinical Center): (Principal Investigators) Cardiology: John Douglas, Jr., MD, Ziyad Ghazzal, MD, Tarek Helmy, MD, Laurence Sperling, MD; Diabetology: Suzanne Gebhart, MD, (Coordinators) Pamela Hyde, RN, Margaret Jenkins, RN, Barbara Grant. Fletcher Allen Health Care, Colchester, VT (Clinical Center, Vanguard Site): (Principal Investigators) Cardiology: David Schneider, MD; Diabetology: Richard Pratley, MD, William Cefalu, MD, (Coordinators) Michaelanne Rowen, RN, CCRC, Linda Tilton, MS, RD, DE. University of Florida, Gainesville, FL (Clinical Center): (Principal Investigators) Cardiology: Carl Pepine, MD, Karen Smith, MD; Diabetology: Laurence Kennedy, MD, (Coordinators) Karen Brezner, CCRC, Tempa Curry, RN, Carol Heissenberg, RN, Natalie Leddy. Fuqua Heart Center/Piedmont Hospital, Atlanta,

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GA (Clinical Center): (Principal Investigators) Cardiology: Carl Jacobs, MD, Spencer King III, MD; Diabetology: David Robertson, MD, (Coordinators) Marty Porter, PhD, Renita Sharma, RN, BSN. The Greater Fort Lauderdale Heart Group Research, Fort Lauderdale, FL (Clinical Center): (Principal Investigators) Cardiology: Alan Niederman, MD; Diabetology: Cristina Mata, MD, (Coordinator) Terri Kellerman, RN. Henry Ford Heart & Vascular Institute, Detroit, MI (Clinical Center): (Principal Investigators) Cardiology: Adam Greenbaum, MD; Diabetology: Fred Whitehouse, MD, (Coordinators) Raquel Pangilinan, RN, Karen Piotrowski, RN. Houston VA Medical Center, Houston, TX (Clinical Center): (Principal Investigators) Cardiology: Gabriel Habib, MD, MS, Issam Mikati, MD; Diabetology: Marco Marcelli, MD, (Coordinators) Emilia Cordero, MS, RN, NP-C, Ruben Valdez, MD. Johns Hopkins Bayview Medical Center, Baltimore, MD (Clinical Center): (Principal Investigators) Cardiology: Sheldon H. Gottlieb, MD; Diabetology: Annabelle Rodriguez, MD, (Coordinator) Melanie Herr, RN. Kaiser-Permanente Medical Center, San Jose, CA (Clinical Center): (Principal Investigators) Cardiology: Ashok Krishnaswami, MD; Diabetology: Lynn Dowdell, MD, (Coordinator) Sarah Berkheimer, RN. Lahey Clinic Medical Center, Burlington, MA (Clinical Center, Vanguard Site): (Principal Investigators) Cardiology: Nicholas Tsapatsaris, MD, Bartholomew Woods, MD; Diabetology: Gary Cushing, MD, (Coordinators) Gail DesRochers, RN, Gail Woodhead, RN, Deborah Gannon, MS, Nancy Campbell, RN MS. University of Maryland Hospital, Baltimore, MD (Clinical Center): (Principal Investigators) Cardiology: J. Lawrence Stafford, MD; Diabetology: Thomas Donner, MD, (Coordinators) Michele Cines, RN, BSN, Kathryn Jeffries, BS, BSN, Margaret Testa, RN, MS, Dana Beach, RN, Cathy Krichten, NP, MS. Mayo Clinic– Rochester, Rochester, MN (Clinical Center, Vanguard Site): (Principal Investigators) Cardiology: Gregory W. Barsness, MD, Kirk Garratt, MD, David Holmes, MD, Charanjit Rihal, MD, Charles Mullaney, MD; Diabetology: Frank Kennedy, MD, Robert Rizza, MD, (Coordinators) Pam Helgemoe, RN, Deborah Rolbiecki, LPN. Mayo Clinic–Scottsdale, Scottsdale, AZ (Clinical Center): (Principal Investigators) Cardiology: Richard Lee, MD; Diabetology: Pasquale Palumbo, MD, (Coordinators) Susan Roston, RN, Lori Wood, RN, Alycia Metcalf, RN. Memphis VA Medical Center/University of Tennessee, Memphis, TN (Clinical Center): (Principal Investigators) Cardiology: Kodangudi Ramanathan, MD, Darryl Weinman, MD; Diabetology: Solomon Solomon, MD; Nephrology: Barry Wall, MD, (Coordinators) Lillie Johnson, RN, Tammy Touchstone, RN, BSN. Mexican Institute of the Social Security, Mexico City, Mexico (Clinical Center): (Principal Investigators) Cariology: Luis Lepe-Montoya, MD; Diabetology: Jorge Escobedo, MD, (Coordinators) Luisa Virginia Buitrón, MD, Beatriz Rico-Verdin, MD, PhD. University of Michigan, Ann Arbor, MI (Clinical Center): (Principal Investigators) Cardiology: Eric Bates, MD, Claire Duvernoy, MD; Diabetology: William Herman, MD, MPH, Rodica Pop-Busui, MD, Martin Stevens, MBBCh, (Coordinators) Ann Luciano, RN, Cheryl Majors, BSN, Patricia Ross, RN, MSN. Mid America Heart Institute, Kansas City, MO (Clinical Center): (Principal Investigators) Cardiology: Steven Marso, MD, James O’Keefe, MD; Diabetology: Alan Forker, MD, William L. Isley, MD, (Coordinators) Paul Kennedy, RN, Margaret Rosson, LPN, CCRC. University of Minnesota/Minnesota Veterans Research Institute, Minneapolis, MN (Clinical Center): (Principal Investigators) Cardiology: Carl White, MD; Diabetology: John Bantle, MD,

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(Coordinators) Deb Johnson, RN, Aimee Muehlen, Christine Kwong, RD, CDE, Julie Dicken, RN, Kristell Reck, RD. Montreal Heart Institute/Hôtel-Dieu-CHUM (Vanguard Site), Montreal, Quebec, Canada (Clinical Center): (Principal Investigators) Cardiology: Martial Bourassa, MD, Jean-Claude Tardif, MD; Diabetology: Jean-Louis Chiasson, MD, (Coordinators) Hélène Langelier, BSc, Johanne Trudel, RN, BSC, Suzy Foucher, RN, BA. Mount Sinai Medical Center, New York, NY (Clinical Center): (Principal Investigators) Cardiology: Michael Farkouh, MD, MSc, Michael Kim, MD; Diabetology: Donald A. Smith, MD, MPH, (Coordinators) Bradley Brown, MS, Dipti Sahoo, MPH, Arlene Travis, RN. Na Homolce Hospital, Prague, Czech Republic (Clinical Center): (Principal Investigators) Cardiology: Lenka Pavlickova, MD, Petr Neuzˇil, MD, PhD, Jaroslav Benedik, MD; Diabetology: Šte˘pánka Stehlíková, MD, (Coordinators) Liz Coling, Stepan Kralovec. New York Hospital Queens, Queens, NY (Clinical Center): (Principal Investigators) Cardiology: David Schechter, MD; Diabetology: Daniel Lorber, MD; Nephrology: Phyllis August, MD, (Coordinators) Maisie Brown, RN, MSN, Patricia Depree, PhD, ANP, CDE. New York Medical College/ Westchester Medical Center, Valhalla, NY (Clinical Center): (Principal Investigators) Cardiology: Melvin Weiss, MD; Diabetology: Irene Weiss, MD, (Coordinators) Maysa Burles, MD, Joanne C. Kurylas, RN, CDE, Jean Baruth, RN, BSN. Northwestern University Medical School, Chicago, IL (Clinical Center): (Principal Investigators) Cardiology: Charles Davidson, MD; Diabetology: Mark Molitch, MD, (Coordinators) Lynn Goodreau, RN, Elaine Massaro, MS, RN, CDE, Fabiola Arroyo, CCT. NYU School of Medicine, New York, NY (Clinical Center): (Principal Investigators) Cardiology: Michael Attubato, MD, Frederick Feit, MD, Ivan Pena-Singh, MD; Diabetology: Stephen Richardson, MD, (Coordinator) Angela Amendola, PA, Bernardo Vargas, BS, Dallas Regan, MSN, NP, Susan Cotton Gray, NP. Ohio State University Medical Center, Columbus, OH (Clinical Center): (Principal Investigators) Cardiology: Raymond Magorien, MD; Diabetology: Kwame Osei, MD, (Coordinators) Cecilia Casey Boyer, RN, Kelly Neidert, RN. University of Ottawa Heart Institute/Ottawa Hospital-Civic Campus, Ottawa, Ontario, Canada (Clinical Center): (Principal Investigators) Cardiology: Richard Davies, MD, Christopher Glover, MD, Michel LeMay, MD, Thierry Mesana, MD; Diabetology: Teik Ooi, MD, Mark Silverman, MD, Alexander Sorisky, MD, (Coordinators) Colette Favreau, RN, Susan McClinton, BSN, Susan Hagar, RN, Melody Dallaire, RN. University of Pittsburgh Medical Center, Pittsburgh, PA (Clinical Center, Vanguard Site): (Principal Investigators) Cardiology: Oscar Marroquin, MD, Howard Cohen, MD; Diabetology: Mary Korytkowski, MD, (Coordinators) Glory Koerbel, MSN, CDE, Deborah Rosenfelder, BS, Carole Farrell, BSN, CCRC, Theresa Toczek, BS. Quebec Heart Institute/Laval Hospital, Sainte-Foy, Quebec, Canada (Clinical Center): (Principal Investigators) Cardiology: Gilles Dagenais, MD; Diabetology: Claude Garceau, MD, (Coordinators) Dominique Auger, RN, Lyne Kelly, RN, Genviève Landry, RN, BSc. University of Sao Paulo Heart Institute, Sao Paulo, Brazil (Clinical Center): (Principal Investigators) Cardiology: Whady Hueb, MD, José Ramires, MD; Diabetology: Bernardo Wajchenberg, MD, (Coordinators) Roberto Betti, MD, Neuza Lopes, MD. St. Joseph Mercy Hospital/Michigan Heart and Vascular Institute and Ann Arbor Endocrinology and Diabetes, PC, Ann Arbor, MI (Clinical Center): (Principal Investigators) Cardiology: Ben McCallister, Jr., MD; Diabetology: Kelly Mandagere, MD, Robert Urbanic, MD, (Co-

ordinators) Carol Carulli, RN, Ruth Churley-Strom, MSN, Penny Wilms, RN, BSN. St. Louis University, St. Louis, MO (Clinical Center): (Principal Investigators) Cardiology: Frank Bleyer, MD; Diabetology: Arshag Mooradian, MD, (Coordinator) Sharon Plummer, NP. St. Luke’s–Roosevelt Hospital Center, New York, NY (Clinical Center): (Principal Investigators) Cardiology: James Wilentz, MD, Judith Hochman, MD, James Slater, MD; Diabetology: Jeanine Albu, MD, (Coordinators) Sylvaine Frances, PA, Deborah Tormey, RN. Texas Health Science at San Antonio/ South Texas Veterans Health Care System, San Antonio, TX (Clinical Center): (Principal Investigators) Cardiology: Robert O’Rourke, MD, Edward Sako, MD, PhD; Diabetology: Janet Blodgett, MD, (Coordinators) Judith Nicastro, RN, Robin Prescott, FNP. University of Texas at Houston, Houston, TX (Clinical Center): (Principal Investigators) Cardiology: Francisco Fuentes, MD, Roberto Robles, MD; Diabetology: Victor Lavis, MD, (Coordinators) Maria Selin Fulton, RN, CDE, Carol Underwood, RN, BSN, Glenna Scott, RN, Jennifer Garza, MA. Toronto General Hospital/University Health Network, Toronto, Ontario, Canada (Clinical Center): (Principal Investigators) Cardiology: Leonard Schwartz, MD; Diabetology: George Steiner, MD, (Coordinators) Kristeen Chamberlain, RN, BScN, Lisa Mighton, RN, Lilianna Stefanczyk-Sapieha, RN, Linda Wright, RN. University of Virginia, Charlottesville, VA (Clinical Center): (Principal Investigators) Cardiology: Ian Sarembock, MD, Eric Powers, MD; Diabetology: Eugene Barrett, MD, (Coordinators) Linda Jahn, RN, MEd, Karen Murie, RN. Washington Hospital Center/Georgetown University Medical Center, Washington, DC (Clinical Center): (Principal Investigators) Cardiology: Kenneth Kent, MD, William Suddath, MD; Diabetology: Michelle F. Magee, MD, (Coordinator) Becky Cockerill, MSN, Vida Reed, RN, CDE. Washington University/Barnes Jewish Hospital, St. Louis, MO (Clinical Center): (Principal Investigators) Cardiology: Richard Bach, MD, Ronald Krone, MD, Majesh Makan, MD; Diabetology: Janet McGill, MD, (Coordinators) Carol Recklein, RN, MHS, CDE, Laurie Chappell, RN, Mary Jane Clifton. Wilhelminen Hospital, Vienna, Austria (Clinical Center): (Principal Investigators) Cardiology: Kurt Huber, MD; Diabetology: Ursula HanuschEnserer, MD, (Coordinators) Nelly Jordanova, MD, Martina Penka, MD. Angiographic Core Laboratory, Stanford University, Stanford, CA: (Principal Investigator) Edwin Alderman, MD, (Staff) Anne Schwarzkopf. Biochemistry Core Laboratory, University of Minnesota, Minneapolis, MN: (Principal Investigator) Michael Steffes, MD, PhD, (Staff) Jean Bucksa, CSL, Maren Nowicki, MT. ECG Core Laboratory, St. Louis University, St. Louis, MO: (Principal Investigator) Bernard Chaitman, MD, (Staff) Terri Belgeri, RN, Jane Eckstein, RN. Economics Core Laboratory, Stanford University, Stanford, CA: (Principal Investigator) Mark A. Hlatky, MD, (Staff) Kathryn A. Melsop, MS. Fibrinolysis Core Laboratory, University of Vermont, Burlington, VT: (Principal Investigator) Burton E. Sobel, MD, (Staff) Michaelanne Rowen, RN, CCRC. Nuclear Cardiology Core Laboratory, University of Alabama at Birmingham, Birmingham, AL: (Principal Investigator) Ami E. Iskandrian, MD, (Staff) Mary Beth Hall, RN, BSN. Diabetes Management Center, Case Western Reserve University, Cleveland, OH: (Director) Saul Genuth, MD, (Staff) Theresa Bongarno, BS. Hypertension Management Center, Lahey Clinic Medical Center, Burlington, MA: (CoDirector) Richard W. Nesto, MD. Hypertension Management Center, New York Hospital Queens, Queens, NY: (Co-Director)

Brooks et al/Hypotheses, Design, and Methods for the BARI 2D Trial

Phyllis August, MD, (Staff) Karen Hultberg, MS. Lifestyle Intervention Management Center, Johns Hopkins Bayview Medical Center, Baltimore, MD: (Co-Director) Sheldon H. Gottlieb, MD. Lifestyle Intervention Management Center, St. Luke’s–Roosevelt Hospital Center, New York, NY: (Co-Director) Jeanine Albu, MD, (Staff) Helene Rosenhouse-Romeo, MS, RD. Lipid Management Center, University of Pittsburgh, Pittsburgh, PA: (Director) Trevor J. Orchard, MBBCh, MMedSci, (Staff) Georgia Pambianco, MPH. North Canton, Ohio: (Safety Officer) Michael Mock, MD. Operations Committee: (Chair) Robert L. Frye, MD, (Members) Maria Mori Brooks, PhD, Sharon Weber Crow, BS, Patrice Desvigne-Nickens, MD, Katherine M. Detre, MD, DrPH,† Abby Ershow, ScD, Saul Genuth, MD, Suzanne Goldberg, RN, MSN,

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David Gordon, MD, PhD, Regina Hardison, MS, Tracey Hoke, MD, ScM, Teresa L. Z. Jones, MD, David Kelley, MD, Sheryl Kelsey, PhD, Richard W. Nesto, MD, Trevor J. Orchard, MBBCh, MMedSci, Dina Paltoo, PhD, MPH. Morbidity and Mortality Classification Committee: (Chair) Thomas Ryan, MD, (Co-Chair) Harold Lebovitz, MD, (Members) Robert Brown, MD, Gottlieb Friesinger, MD, Edward Horton, MD, Jay Mason, MD, Jack Titus, MD, PhD, Lawrence Wechsler, MD. Data and Safety Monitoring Board: (Chair) C. Noel Bairey-Merz, MD, (former Chair) J. Ward Kennedy, MD, (Executive Officer) David Gordon, MD, PhD, (Members) Elliott Antman, MD, John Colwell, MD, PhD, Sarah Fowler, PhD, Curt Furberg, MD, Lee Goldman, MD, Bruce Jennings, MA, Scott Rankin, MD.